REVIEW
published: 08 March 2021
Edited by:
Kai-Feng Xu,
Peking Union Medical College
Hospital (CAMS), China
Reviewed by:
Xiaowen Hu,
Anhui Provincial Hospital, China
Paola Rottoli,
University of Siena, Italy
Itziar Astigarraga,
Cruces University Hospital, Spain
*Correspondence:
Elzbieta Radzikowska
e.radzikowska@wp.pl
orcid.org/0000-0002-2585-8594
Specialty section:
This article was submitted to
Pulmonary Medicine,
a section of the journal
Frontiers in Medicine
Received: 12 July 2020
Accepted: 21 December 2020
Published: 08 March 2021
Citation:
Radzikowska E (2021) Update on
Pulmonary Langerhans Cell
Histiocytosis. Front. Med. 7:582581.
doi: 10.3389/fmed.2020.582581
Frontiers in Medicine | www.frontiersin.org
doi: 10.3389/fmed.2020.582581
Update on Pulmonary Langerhans
Cell Histiocytosis
Elzbieta Radzikowska*
III Department of Lung Diseases and Oncology, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland
Pulmonary Langerhans cell (LC) histiocytosis (PLCH) has unknown cause and is a
rare neoplastic disorder characterized by the infiltration of lungs and various organs
by bone marrow-derived Langerhans cells with an accompanying strong inflammatory
response. These cells carry somatic mutations of BRAF gene and/or NRAS, KRAS,
and MAP2K1 genes, which cause activation of the mitogen-activated protein kinase
(MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. PLCH occurs
predominantly in young smokers, without gender predominance. Lungs might be
involved as an isolated organ or as part of a multiorgan disease. High-resolution
computed chest tomography plays an outstanding role in PLCH diagnosis. The
typical radiological picture of PLCH is the presence of small intralobular nodules,
“tree in bud” opacities, cavitated nodules, and thin- and thick-walled cysts, frequently
confluent. Histological examination of the lesion and demonstration of characteristic
eosinophilic granulomas with the presence of LCs that display antigen CD1a or CD207
in immunohistochemistry are required for definite diagnosis. Smoking cessation is the
most important recommendation for PLCH patients, but treatment of progressive PLCH
and multisystem disease is based on chemotherapy. Recently, new targeted therapies
have been implemented.
Keywords: pulmonary Langerhans cell histiocytosis, adults, lung, BRAF, MAPK
INTRODUCTION
Pulmonary Langerhans cell (LC) histiocytosis (PLCH) is a rare neoplastic disorder of unknown
etiology, characterized by the infiltration of the lungs and various organs by bone marrow-derived
LCs with an accompanying strong inflammatory response (1). These cells carry somatic mutations
of the BRAF gene and/or NRAS, KRAS, and MAP2K1 genes, which cause activation of the
mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling
pathway (2–5).
The histiocytic diseases have been reclassified into five categories; LCH is considered a member
of group L, along with Erdheim–Chester disease, indeterminate cell histiocytosis, and mixed
LCH/Erdheim–Chester disease (1, 6). PLCH occurs predominantly in young smokers and shows no
predominance in either sex. The lungs may be involved as isolated organs or as part of a multisystem
disease (7). Proliferating LCs form nodular lesions of various sizes, which infiltrate neighboring
tissues and damage their structure. In adults, LCH most commonly affects the lungs, bones, skin,
and pituitary gland. The involvement of lymphopoietic organs (e.g., lymph nodes, liver, spleen, and
bone marrow), alimentary system, and central nervous system (CNS) is rare. In the course of LCH,
pulmonary lesions may be isolated, occur after chronic systemic disease, or are an initial sign of
disease. The isolated pulmonary form of LCH is observed in approximately 50–70% of patients
with PLCH (8–11).
1 March 2021 | Volume 7 | Article 582581
Radzikowska
Single-system LCH (SS-LSH) comprises single or multiple
involvement of the following single organs or systems:
Bone, with involvement of a single or multiple bones and
many foci in many bones;
Skin;
Lymph nodes, excluding lymph nodes that drain the area
of histiocyte infiltration or multiple lymph nodes (i.e., more
than one lymph node group);
Hypothalamus–hypophysis/CNS;
Isolated pulmonary involvement;
Other, with involvement of oral mucosa, thyroid, thymus,
or intestine.
Multisystem LCH (MS-LCH) comprises disease in which two
or more organs or systems are affected:
Involvement of critical organs, e.g., hemopoietic system,
spleen, liver;
No involvement of critical organs.
The involvement of specific areas and bones [e.g., vertebrae
(possible compression spinal fracture and damage to the spinal
cord), orbital bones, mastoid process, sphenoid bone, and
temporal bones with transition into soft tissue (possible injury
to facial nerves and pituitary gland)] is associated with the risk of
CNS involvement, which impacts decisions regarding treatment
(7, 12).
Previously, the lungs were considered as a “risk organ,” but
multivariable analysis of cohorts of 420 children with MS-
LCH showed that lung involvement was not the significant
prognostic variable (13). However, patients with lung lesions
have a high risk of developing life-threatening complications
(e.g., pneumothoraces, pulmonary infections). Recently, Le Louet
et al. (14) presented the assessment of French LCH registry,
and it was found that severe lung involvement in children was
associated with high mortality. These findings suggested revision
of treatment guidelines for this group of patients.
EPIDEMIOLOGY
LCH has an estimated prevalence in adults of 1–2/1,000,000.
However, there have been few population-based epidemiological
studies regarding this disease. In Japanese hospitalized patients,
the prevalence rates of PLCH were reported to be 0.07/100,000
in women and 0.27/100,000 in men. PLCH is presumed to affect
approximately 5% of patients undergoing open lung biopsy. The
prevalence of PLCH may be underestimated due to the nature of
the disease (7, 15).
PLCH affects young people in the third and fourth decades
of life, with no sex predominance. Approximately 90 to
95% of patients with PLCH are tobacco smokers (16, 17).
Abbreviations: ARAF, A serine/threonine kinase; AKT, serine/threonine kinase;
BRAF, B serine/threonine kinase; 2-CDA, 2-chloro-2’-deoxyadenosine; CNS,
central nervous system; ERK, extracellular signal-regulated kinase; HRCT,
High-resolution computed tomography; LAM, lymphangioleiomyomatosis; LC,
Langerhans cell; LCH, Langerhans cell histiocytosis; MAPK, mitogen-activated
protein kinase; MS-LCH- multisystem Langerhans cell histiocytosis; mTOR,
mechanistic target of rapamycin; P, phosphorylation; PIK, phosphatidylinositol
kinase; PIP-1, phosphatidylinositol monophosphate; PIP-2, phosphatidylinositol
biphosphate; PLCH, pulmonary Langerhans cell histiocytosis; PTEN, phosphate
and tensin homolog; SS-LCH single system Langerhans cell histiocytosis.
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
Recently, it was noticed that 20–33% of patients smoked
both cigarettes and cannabis [(18), personal observations].
The intensity and smoking duration do not influence the
development of PLCH. Isolated PLCH in children is extremely
rare; the disease is reportedly associated with passive exposure
to tobacco smoke in the majority of pediatric patients,
and ∼10–30% of children with multisystem LCH exhibit
pulmonary lesions (11, 19). Familial occurrence of LCH has been
reported, but no genetic predisposition toward LCH has been
found (7).
PATHOGENESIS
There have been many investigations regarding the pathogenesis
of LCH; the finding that dendritic cells with mutations in MAPK
pathway genes contribute to the development of the disease has
yielded new insights. Dendritic cells are a heterogeneous group
of cells, which mainly serve to process and present antigens to
immune cells. Normal LCs are present in the skin, as well as
beneath the epithelia of the bronchial tree and other mucosae
(3, 6). Toll-like receptors, expressed on pathogen-sensing cells,
and factors released from damaged or dying cells, stimulate
the activity of normal LCs. Subsequently, the immunological
response involves the migration of activated dendritic cells to
the nearest lymph nodes and presentation of antigens to naive T
lymphocytes. In addition, tolerance to harmless inhaled antigens
is mediated by normal LCs (20).
Tobacco smoke plays a major role in the development of
PLCH (21). It causes inflammatory cell accumulation in the
lungs; these cells include LCs, which release cytokines such as
tumor necrosis factor alpha, interleukin 1 beta, granulocyte-
macrophage colony-stimulating factor, transforming growth
factor beta, and the dendritic cell chemokine (chemokine
ligand 20) (22). In addition, bronchial epithelial cells and
fibroblasts release granulocyte-macrophage colony-stimulating
factor, which is a strong mitogenic factor for LCs.
Moreover, PLCH lesions exhibit elevated expression of
osteopontin, a glycoprotein that induces chemotactic activity
in macrophages, monocytes, and dendritic cells, including LCs.
Activated pathological LCs show strong lymphocyte-stimulating
properties and are characterized by elevated expression of CD40,
CD80, and CD86. Previous studies have yielded inconsistent
results regarding the importance of interleukin-17 released by
T lymphocytes in the pathogenesis of histiocytic lesions. This
cytokine promotes the development of giant cells and formation
of granulomas. Elevated expression of the antiapoptotic protein,
Bcl-xL, within histiocytic granulomas maintains the pathogenic
process (23).
In addition to inflammation, granuloma formation is
accompanied mPAP, mean pulmonary arterial presure; by
remodeling of the lung parenchyma. Cystic destruction of the
lung is presumably caused by activation of metalloproteinases
2 and 9, produced by dendritic cells, LCs, and monocytes.
Moreover, elevated expression of transforming growth factor beta
released by granuloma cells causes fibrotic lesions (12).
There have been a number of investigations regarding the
pathogenesis of PLCH. Inflammatory cell accumulation and the
2 March 2021 | Volume 7 | Article 582581
Radzikowska
presence of LCs with dysfunctional apoptosis, as well as clonal
proliferation, have been associated with the onset of PLCH.
Identification of the role of the RAS/MAPK signaling pathway
in the pathogenesis of LCH was a key discovery regarding the
pathogenetic mechanism of this disorder (24). This pathway
transmits proliferative signals from the cell surface via the RAS
pathway to phosphorylate MAPK and ERK, which transmit
signals to the nucleus. The MAPK pathway regulates the activities
of many enzymatic proteins and transcription factors. Activating
mutations of the BRAF, ARAF, MAP2K1, N/K/HRAS, and
PIK3CA genes have been found in patients with PLCH (25–
27) (Figure 1). The BRAF V 600E mutations were found in
50% of LCH pulmonary nodules and MAP2K1 in an additional
20% of cases (26). Moreover, whole-exome sequencing analysis
revealed MAP2K1 mutations in seven of 21 BRAF-wild-type
LCH biopsy tissue samples, but not in BRAF-mutant specimens
(5). The activation of ERK was detected in >90% of patients
with LCH. In patients with multisystem LCH, mutation of the
BRAF V 600E gene may occur in myeloid cells; in patients with
single-system LCH, mutations may occur in cells originating
from peripheral lesions (28). The single-cell analysis showed
cellular, transcriptomic, and epigenomic heterogeneity among
LCH cells, which ware connected with the development of
LCH lesions. LCH cells share enrichment of genes involved in
interferon (IFN) signaling and antigen presentation, indicating
the inflammatory nature of the disease. In addition, genes
involved in cell cycle pathways and DNA repair were presented.
It is suggested that interindividual differences in subsets of LCH
cells may be connected with clinical presentation of the disease.
Validation of the differences in LCH subset composition in bulk
RNA sequencing, immunohistochemistry, immunofluorescence
imaging in a large cohort of LCH patients might be helpful in
patient management (29).
FIGURE 1 | MEK-mitogen activated protein kinase–extracellular signal-regulated kinase (ERK) signaling cascade of the mitogen-activated protein kinase (MAPK)
pathway and phosphoinositide 3-kinase (PI3K)–AKT-serine/threonine protein kinase Akt pathway. Diagram of RAS protein activation.
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
Mutations in genes involved in the MAPK pathway related
to precursors of distinct macrophage types (i.e., bone marrow or
yolk sac) result in the occurrence of an overlapping syndrome of
LCH and Erdheim–Chester disease or chronic myeloid leukemia.
Notably, PLCH was recently recognized as a neoplasm with a
strong inflammatory component (30).
CLINICAL PRESENTATION
Respiratory Symptoms
Patients with PLCH exhibit dry cough (50–70%), reduced
exercise tolerance (40–80%), exertional dyspnea (40–87%),
fatigue (50–80%), weight loss (20–30%), chest pain (10–30%),
night sweats (10–20%), and fever (10–15%). Approximately
10–30% of affected patients are diagnosed following incidental
pneumothorax. Pneumothorax occurs during the course of
disease in 30–45% of affected patients (17, 31). Changes are found
incidentally on routine chest X-rays without symptoms in 5–25%
of affected patients. Dyspnea at rest and characteristics of right-
ventricular circulatory failure occur in the late stages of PLCH.
More than 10% of patients with PLCH develop pulmonary
hypertension; it is not always related to the exacerbation of
pulmonary lesions but may be due to the involvement of
pulmonary vessels that occurs during the course of the disease
(9, 11). Pulmonary hypertension and dynamic hyperinflation
are the most important factors that limit exercise capacity in
PLCH patients (32). Moderate or severe pulmonary hypertension
[mean pulmonary arterial pressure (mPAP) >35 mmHg] was
revealed in 92% of the PLCH patients who presented for lung
transplantation (33).
Between 25 and 50% of patients without pulmonary
symptoms at the time of presentation show symptoms related
3 March 2021 | Volume 7 | Article 582581
Radzikowska
to other organ involvement, such as polyuria–polydipsia (20–
30%), bone pain (20–50%), and oral mucosa or skin lesions
(∼10%). Initial evaluation of patients with LCH requires whole-
body assessment. Symptoms typically arise 6–20 months prior
to recognition of the disorder; in some affected patients, the
diagnosis is established after many years of observation. Patients
with spontaneous pneumothorax as an initial symptom of the
disease are reportedly younger, more frequently men, and exhibit
greater respiratory impairment compared with those who do not
have pneumothorax (17).
Radiological Findings
Chest Radiography
Standard chest radiography has limited value, as multiple lesions
may be small. In patients with advanced disease, nodular,
reticular, and cystic lesions are visible in the middle and upper
lung fields (Figure 2). Lung volumes are typically preserved but
may be diminished in patients with a history of pneumothorax
and pleurodesis. Enlargement of the hilar and mediastinal lymph
nodes is present in approximately 10% of affected patients (11).
Computed Tomography
High-resolution computed tomography (HRCT) plays a major
role in the diagnosis of PLCH (7, 34). The typical findings
are centrilobular nodules (frequently with a “tree-in-bud”
appearance), nodules with or without a lacuna, and initially
thick-walled cysts of various shapes (these may be isolated or
confluent with a “cloverleaf ” appearance) (Figures 3–5). As the
disease progresses, the cysts become larger and thin-walled.
Lesions have a characteristic distribution, with predominance in
the upper and middle parts of the lungs; the costophrenic angles
FIGURE 2 | X-ray film of a pulmonary Langerhans cell histiocytosis (PLCH)
patient. Multiple reticular and nodular changes in the upper and middle parts
of both lungs, with an increase in lung volume.
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
are spared (>90%). In children, both lungs are symmetrically
affected and lesions may be present in the lower lobes (14). In
some patients, different degrees of pneumothorax are present. In
patients with PLCH, other radiological symptoms of smoking-
related diseases are often visible (e.g., emphysematous bullae or
ground-glass opacities). Enlarged lymph nodes may be present
in approximately 10% of affected patients. Signs of pulmonary
hypertension, megalocardia, and enlarged pulmonary trunk are
observed in patients with advanced disease (35).
Positron Emission Tomography
Positron emission tomography with 18 F-fluorodeoxyglucose has
limited value in the assessment of patients with PLCH. Only 20–
25% of patients show higher 18 F-fluorodeoxyglucose uptake in
the lungs, particularly in thick-walled cysts and nodular lesions.
Positron emission tomography is more sensitive than CT in terms
FIGURE 3 | High-resolution computed tomography (HRCT) scan of a
pulmonary Langerhans cell histiocytosis (PLCH) patient. Multiple intralobular
nodules, nodules with cavitations, and small nodular lesions in both lungs.
FIGURE 4 | High-resolution computed tomography (HRCT) scan of a
pulmonary Langerhans cell histiocytosis (PLCH) patient. Multiple cystic lesions,
frequently confluent with bizarre shapes.
4 March 2021 | Volume 7 | Article 582581
Radzikowska
FIGURE 5 | High-resolution computed tomography (HRCT) scan of a
pulmonary Langerhans cell histiocytosis (PLCH) patient. Large confluent cystic
lesions in both lungs.
of identifying bone lesions, particularly those that are subclinical,
as well as those that involve lymph nodes, liver, spleen, or thyroid.
Positron emission tomography is reportedly sensitive for the
assessment of early response to treatment and disease relapse
(36, 37).
Laboratory Tests
The results of laboratory tests are usually unremarkable.
However, patients with PLCH often show elevated levels of
serum inflammatory markers. Serum hyperosmolarity with lower
urine specific gravity and hypoosmolarity are observed in
patients with diabetes insipidus. Elevated serum levels of hepatic
enzymes and bilirubin are characteristic of liver involvement
(7). Fluid phase biopsy is valuable for the assessment of
BRAF mutations in patients who are potential candidates for
targeted therapy.
Pulmonary Function Testing
Patients with PLCH exhibit various patterns of ventilation
disorders. Initially, approximately 20% of affected patients have
normal values on pulmonary function tests. Obstruction with
hyperinflation is the main abnormality and can often be reversed
to some degree. Restricted breathing is uncommon and mainly
affects individuals with recurrent pneumothorax and pleurodesis.
The most common abnormality is reduced diffusing capacity
of the lungs for carbon monoxide, which is observed in
approximately 70–90% of affected patients. The 6-min walk test
is a useful examination; desaturation during exercise is a sensitive
marker of lung impairment in patients with less advanced disease,
and a reduced walking distance is observed in patients with
advanced disease (17, 38, 39).
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
Bronchoscopy and Bronchoalveolar Lavage
Bronchoscopy is typically performed to exclude other disorders,
especially infections. The diagnostic value of transbronchial
biopsy is limited and estimated at 10–50% due to focal
distribution of lesions, despite the bronchiolocentric nature of
the disease (40, 41). Transbronchial biopsy is most useful in
patients with nodular lesions but in patients with cystic lesions
is associated with a high risk of pneumothorax. A new technique
for lung tissue sampling, cryobiopsy, yields a diagnosis in ∼70%
of patients with interstitial lung disease. The value of this technic
in PLCH is under evaluation because in only a few cases has
diagnosis of PLCH been established by cryobiopsy (42, 43). The
presence of >5% cells with CD1a expression in bronchoalveolar
lavage (BAL) fluid with a typical radiological pattern on chest
HRCT is specific for PLCH but is detected in only 0–25% of
affected patients (44). Auerswald et al. (45) noticed that all their
six patients with histologically proven histiocytosis displayed
more than 5% CD1-positive cells, but Torre and Harari (46)
were able to establish PLCH in four (25%) out of 16 patients
on the basis of BAL assessment. Similarly, only three (38%)
out of eight patients with PLCH presented by Baqir et al. (41)
and 10 (25%) out of 40 patients presented by Elia et al. (11)
in whom BAL was performed displayed the presence of CD1a-
positive cells over 5%. In our group of 38 patients with PLCH,
only in eight (21%) did BAL assessment have a diagnostic
value (47).
Lung Biopsy
Open lung biopsy is the gold standard for a definitive diagnosis
of PLCH. In patients with LCH confirmed by histological
examination of specimens obtained from other foci (e.g., skin,
mucosa, or bones), it is not necessary to confirm pulmonary
lesions (7).
Histological Examination
PLCH has a focal, bronchiolocentric localization. Initially,
inflammation with eosinophilic granuloma formation occurs
near small bronchi and bronchioles, destroying their walls; it
exhibits varying degrees of extension into the adjacent lung
interstitium. Frequently, macrophages with dark inclusions are
observed; these macrophages are characteristic of exposure
to inhaled fumes, mainly tobacco smoke. Nodules contain a
mixture of inflammatory cells, such as T cells, macrophages,
monocytes, and LCs; these LCs are relatively large, with
a pale, slightly eosinophilic cytoplasm and a convoluted
nucleus that exhibits a longitudinal crease resembling a coffee
bean. Electron microscopic examination shows pentalammelar
structures (consisting of lectin) in the cytoplasm associated
with the cell membrane; these so-called Birbeck granules are
characteristic of LCs. These structures can also be identified by
immunohistochemistry using antibodies against langerin (i.e.,
CD207). LCs show CD1a expression, which is necessary for
diagnosis (24). The expression of S-100 protein is not specific
but may be present. Inflammatory eosinophilic granulomas may
be observed, depending on the stage of disease progression. The
central part of the nodule has a lacuna, which is presumably
a component of the remaining bronchiole lumen or the
5 March 2021 | Volume 7 | Article 582581
Radzikowska Update on PLCH

effect of cytokine and metalloproteinase-mediated destruction. TABLE 1 | Diseases with a cystic pattern of lung lesions.
Subsequently, the inflammation regresses; however, fibrosis
• Pulmonary Langerhans cell histiocytosis
develops in the form of stellar scars or confluent cystic
• Lymphangioleiomyomatosis (LAM)
cavities in the fibrous ring. At this stage, LCs are absent. ◦
Sporadic LAM
In LCH lesions, LCs constitute 1–80% of cells (mean ∼8%) ◦
Tuberous sclerosis complex LAM
(3). Lung specimens from patients with PLCH may also show
• Birt–Hogg–Dubé syndrome
signs of other smoking-related diseases, such as bronchiolitis,
• Erdheim–Chester disease
desquamative interstitial pneumonia, respiratory bronchiolitis
• Lymphatic disorders
with accompanying interstitial lung disease, or emphysema.
In patients with advanced disease, the internal walls of both
◦
Lymphocytic interstitial pneumonia

arteries and veins are thickened, resulting in pulmonary

◦
Light-chain deposition disease

hypertension (48).
◦
Amyloidosis
◦
Hyper-IgE syndrome
Patients who qualify for targeted therapy must be tested for
• Genetic disorders
mutations in the BRAF, ARAS, NRAS, KRAS, and MAP2K genes ◦
Ehlers–Danlos syndrome
(5). Moreover, as a novel diagnostic technique for monitoring
◦
Neurofibromatosis
patients undergoing treatment with BRAF inhibitors, analysis of
◦
Marfan syndrome
BRAF V600E gene mutations in cell-free DNA in serum has been
◦
Proteus syndrome
implemented (49, 50).
• Congenital pulmonary airway malformations
• Infections
DIAGNOSIS ◦
Respiratory papillomatosis
◦
Staphylococcal pneumonia
Definite diagnosis of PLCH requires adequate clinical ◦
Pneumocystis jirovecii
presentation and the identification of LCs in biopsy specimens ◦
Endemic fungal diseases (coccidiomycosis, paragonimiasis)
that exhibit either CD207 (langerin) or CD1a.
• Emphysema
Probable diagnosis of PLCH relies on clinical presentation
• Alpha-1 antitrypsin deficiency
confirmed radiologically (characteristic cysts and nodules
• Post-traumatic pseudocysts
mainly observed in upper and middle lung fields on chest
• Pulmonary neoplasms
CT). Histological verification of all extrapulmonary lesions is ◦
Adenocarcinoma
recommended (7). ◦
Lymphoma
◦
Mesenchymal hamartoma
Differential Diagnosis ◦
Pleuropulmonary blastoma
Disorders that should be taken into account while diagnosing the
• Sarcomas
patients with cystic pulmonary lesions are presented in Table 1. ◦
Angio and osteosarcomas
In patients with nodular lesions, diseases such as neoplasms, ◦
Synovial cell sarcoma
sarcoidosis, hypersensitivity pneumonitis, and infections are in ◦
Leiomyosarcoma
the scope of differential diagnosis (7).
◦
Rhabdomyosarcoma
◦
Endometrial stromal sarcoma
TREATMENT ◦
Wilms tumor
◦
Ewing sarcoma
Treatment of LCH depends on the disease activity and affected • Metastatic tumors
organs, including lesions in critical organs and high-risk bones, ◦
Adenocarcinoma of genitourinary and gastrointestinal tract
as well as the degree of damage (Figure 6). ◦
Breast Cancer
◦
Cancers of the head and neck
Smoking Cessation
Because of the crucial role of tobacco smoke in the
development of PLCH, smoking cessation is the most
important recommendation for affected patients. In ∼50% is becoming a challenge for both patients and doctors [(52),
of patients with isolated PLCH, smoking cessation leads to personal observation].
partial regression and subsequent stabilization of the disorder
without immunosuppressive therapy (16, 51). However, patients Glucocorticosteroids
require systematic follow-up examinations because reactivation Systemic corticosteroid therapy has been advised for many
of the disease can occur in the lungs or other organs. Thus far, years; it has been reportedly associated with symptomatic,
no biological markers have been found to identify patients in radiological, and functional improvements. However, there
whom smoking cessation would be sufficient and patients in have been insufficient studies to determine the appropriate
whom the disease is likely to progress despite smoking cessation. corticosteroid dose and duration of treatment, as well as
Cessation of both cigarette smoking and marijuana smoking comparative studies with respect to smoking cessation. It is

Frontiers in Medicine | www.frontiersin.org 6 March 2021 | Volume 7 | Article 582581

Radzikowska
FIGURE 6 | Management of pulmonary Langerhans cell histiocytosis (PLCH).
possible that some effects of therapy are due to smoking cessation,
rather than steroid treatment (10). In addition, relapse after
treatment is common (∼80%); long-term corticosteroid therapy
is associated with many (sometimes severe) adverse effects.
Therefore, this treatment is no longer recommended. However,
inhaled corticosteroids may be useful for treatment of patients
with reversible obstruction (7).
Chemotherapy
Various chemotherapy regimens have been proposed for use in
children with LCH, but they have failed to show satisfactory
results in adults. The disease has a diverse clinical course
in adults, particularly in patients with isolated PLCH, and
many drugs are differently tolerated (53–55). Vinblastine,
methotrexate, mercaptopurine, and etoposide have shown
benefits in some patients with multisystem LCH, but their
effects in patients with isolated PLCH are controversial (56).
A retrospective study involving a population of 35 adults with
LCH (17 patients with pulmonary involvement) treated with
vinblastine and steroids showed a response rate of 70%; however,
the relapse rate was 40% during the 5-year follow-up period (57).
No improvements in ventilation parameters due to vinblastine
treatment were observed in any patient. Cantu et al. (58) reported
that vinblastine treatment was less effective than cladribine or
cytarabine in adult patients with multifocal bone disease (28%
had pulmonary lesions). However, the effects of these treatments
on lung function parameters were not discussed. Recently, Néel
et al. (59) reported an overall response rate of 91% in 22 patients
treated with cladribine; however, disease progression occurred in
30% of these patients during the 5-year follow-up period.
Saven and Burian (60) reported that 2-chloro-2′ -
deoxyadenosine (2-CDA) had beneficial effects in 12 patients
(six with lung involvement), affording an overall response rate of
75%. Grobost et al. (61) reported that cladribine (three or four
courses) improved pulmonary function parameters in four of
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
five patients with PLCH; however, one of these patients exhibited
relapse. Pardanani et al. (62) and Adam et al. (63) in five and
seven patients with PLCH who received 2-CDA, respectively
reported over than 60% response rate.
Cladribine treatment in adult PLCH patients is a
subject of an ongoing phase II clinical trial (NCT01473797,
www.ClinicalTrials.gov). The most frequently observed severe
adverse event during the course of cladribine treatment is
cytopenia, whereas the most severe event associated with
vinblastine is neuropathy. For patients with disease progression
after cladribine treatment, salvage therapy is cytarabine
administered at a dose of 100 mg/m2 on five consecutive days
at 4-week intervals. Another phase II trial (NCT04121819,
www.ClinicalTrials.gov) to investigate the efficacy and safety of
cytarabine in adult patients with LCH is currently underway.
Notably, the preferred chemotherapeutic regimen in patients
with brain lesions is cytarabine and cladribine because both
drugs cross the blood–brain barrier.
Clofarabine is another drug that is effective as salvage therapy
in children and is the subject of another ongoing phase II clinical
trial (NCT02425904). In addition, severe lung cystic lesions
and chemotherapy, particularly with concomitant corticosteroid
treatment, are predisposing factors to opportunistic infections,
particularly Pneumocystis jiroveci pneumonia. Grobost et al.
(61) recommended that sulfamethoxazole/trimethoprim and
valaciclovir prophylaxis should be administered during cessation
of 2-CDA treatment, as well as for 6 months afterward.
Targeted Therapies
Vemurafenib and Other BRAF Inhibitors
The presence of mutations in genes involved in the MAPK
pathways in patients with PLCH implies that targeted therapy
may be useful. Vemurafenib, a BRAF kinase inhibitor, is
reportedly an effective treatment in patients with LCH (64, 65,
70). However, this drug did not eliminate all LCs; discontinuation
of treatment resulted in disease progression. Diamond et al.
(67) reported the beneficial effects of vemurafenib in a group
of 22 patients with Erdheim–Chester disease and four patients
with LCH; these patients exhibited a 2-year progression-free
survival rate of 86% and an overall survival rate of 96%.
Notably, the patients with LCH showed a particularly good
response. Bhatia et al. (68) reported a partial response in patients
with refractory Erdheim–Chester disease overlapping with LCH
during treatment with another BRAF inhibitor, dabrafenib.
Recently, Hazim et al. (66) presented results of treatment with
vemurafenib and dabrafenib in six adult patients with LCH.
Complete and partial responses were noticed in 30 and 50% of
patients, respectively (Table 2).
In a study of children with LCH performed in France, the
presence of BRAF mutations was associated with a weaker
response to first-line treatment (vinblastine and steroids) and
second-line treatment, as well as a higher proportion of
recurrence (65, 71). However, no correlations were found
between BRAF mutations, clinical presentation, and prognosis in
adults (5).
7 March 2021 | Volume 7 | Article 582581
Radzikowska Update on PLCH

TABLE 2 | Targeted therapies in LCH adult patients. time of the first ipsilateral recurrence and the overall number of
Study Trial Patients BRAF Time of Response
pneumothorax recurrences were similar after conservative and
inhibitor response thoracic surgical treatments. Pneumothorax recurrences may be
assessment linked with active disease (18). Notably, pleurodesis does not
Hyman (70) Phase 2 13 ECD Vemurafenib 2 months ORR-43%
constitute a contraindication for lung transplantation (7).
1 LCH
Diamond Phase 2 22 ECD Vemurafenib 2–40 months ORR-61% Treatment of Pulmonary Hypertension
et al. (67) 4 LCH
The progression of PLCH leads to the destruction of
Bhatia (68) Retrospective 7 ECD Dabrafenib 2–40 months ORR-
4 ECD/LCH 100%
lung parenchyma with elements of fibrosis, as well as the
Diamond Prospective 12 ECD Cobimetinib 12 months ORR-89% development of pulmonary hypertension. In a small proportion
et al. (69) 2 LCH of patients, those with stable ventilation parameters may exhibit
Hazim (66) Retrospective 6 LCH 3 Vemurafenib 4–27 months CR-33%
3 Dabrafenib PR-50%
pulmonary hypertension.
Oxygen treatment is the main recommendation for this
CR, complete response; ECD, Erdheim–Chester disease; LCH, Langerhans cell group of patients. Furthermore, drugs that lower pulmonary
histiocytosis; ORR, overall response rate; PR, partial response.
artery blood pressure (e.g., inhibitors of phosphodiesterase and
endothelin receptor, as well as prostacyclin) were shown to
have beneficial effects in patients with PLCH who exhibited
Mitogen-Activated Protein Kinase Inhibitors pulmonary hypertension (78). Also other small series of patients
Drugs that inhibit mitogen-activated kinase 1 (MEK1) and 2, and case reports presented beneficial effects of pulmonary
both downstream of BRAF, were shown to be beneficial in antihypertensive therapies; however, it is not proven as standard
patients with LCH who exhibited MAP2K1 deletion. Lorillion treatment and should be delivered in very experienced centers
et al. (72) reported a good response to trametinib. Cobimetinib, (79, 80).
a MEK1 and 2 inhibitor, was the subject of a clinical trial in
patients with various histiocytic disorders. All patients showed Lung Transplantation
a response to this treatment; the relapse rate was only 10% at 1 Lung transplantation is a salvage therapeutic option for patients
year (69). Studies regarding melanoma cells harboring mutations with features of respiratory failure and those developing
in genes involved in the MAPK pathway showed that dual pulmonary hypertension. The prognosis of patients undergoing
inhibition of BRAF and MEK was more effective and less toxic transplantation does not significantly differ from that of patients
than monotherapy with a BRAF inhibitor. Awada et al. (73) with other interstitial lung diseases. The 1-year survival rate is
reported beneficial results of this treatment in adult patients with 75%; notably, >50% of patients survive for 5 years. Patients with
multisystem LCH. Multiple clinical trials involving BRAF and multisystem LCH and lung involvement have a worse prognosis
other RAS pathway inhibitors in adults and children with LCH after transplantation, and recurrence of LCH in the transplanted
are currently underway (www.ClinicalTrials.gov). organ has been found in approximately 20% of affected patients
(33). Based on 87 transplant patients, Wajda et al. (81) reported
Tyrosine Kinase Inhibitors outcomes similar to those of prior studies; 1-year, 5-year, and 10-
Contradictory results have been reported regarding the effects year survival rates were 85, 49, and 22%, respectively. Moreover,
of imatinib treatment. Montella et al. (74) and Janku et al. the median survival was significantly better for women than for
(75) reported beneficial effects of this drug in a 37-year-old men (mean survival time, 9.3 vs. 3.9 years).
woman with multisystem LCH and in two adult patients with
multisystem LCH, respectively. However, the follow-up periods Follow-Up Examination
in these patients were both shorter than 2 years. In contrast, Patients with PLCH should undergo systematic follow-up
Wagner et al. (76) reported treatment failure in two patients examinations, initially performed after 3–4 months with
treated with imatinib. subsequent evaluations at intervals of 3–12 months, depending
on disease activity (7). HRCT is not necessary at every follow-up
Pneumothorax examination because it is not highly sensitive for evaluation of
Pneumothorax, as the first symptom of PLCH, is observed disease activity (34). Similarly, assessments of organs other than
in 10–30% of affected patients. In addition, these patients the lungs are not required; however, these evaluations should be
have a greater probability of pneumothorax recurrence (∼60%). performed in the event of new symptoms. Pulmonary function
Generally, 30–40% of patients develop this condition during tests are important in follow-up assessment of patients with
long-term observation. Moreover, this group often includes PLCH. Deterioration of exercise tolerance or the presence of new
young men who smoke fewer cigarettes and whose lung symptoms requires close examination. Participation in tobacco
function is more affected by the disease. These data support and marijuana cessation programs is highly recommended.
the recommendation that HRCT should be performed in all
patients with spontaneous pneumothorax to identify patients PROGNOSIS
with possible PLCH (17, 31, 77).
Pleurodesis should be recommended after the first episode The natural course and prognosis of PLCH are unpredictable
of pneumothorax. However, it was recently reported that the and variable. Spontaneous regression and/or stabilization of

Frontiers in Medicine | www.frontiersin.org 8 March 2021 | Volume 7 | Article 582581

Radzikowska
the disease after smoking cessation, as well as the presence of
addiction to substances other than tobacco in some patients,
results in loss to follow-up for many patients; this may influence
survival assessment. However, patients with PLCH were reported
to exhibit lower mean survival compared to sex- and age-
matched members of the general population (7). Vassallo et al.
(9) observed a median survival of 12.5 years in adult patients with
biopsy-proven PLCH.
Reduced spirometry parameters, low diffusing capacity
of the lungs for carbon monoxide, severe cystic lesions
detected on HRCT, low oxygen arterial pressure, older age,
pulmonary hypertension, and multisystem LCH are negative
prognostic factors. Moreover, a higher St. George’s Respiratory
Questionnaire (SGRQ) score and continued tobacco smoking
have negative impacts on survival. Tazi et al. (16) presented an
early decline of pulmonary function parameters (over 15%) in
40% of newly diagnosed PLCH patients, but in only 10% of them,
progression of pulmonary lesions was noticed.
Recently, severe lung involvement in children was recognized
as a factor that substantially influences the course of the disease
and survival. Early administration of new targeted LCH therapies
and viral infection prophylaxis are suggested (14).
Patients with PLCH also have a higher risk of
infections; therefore, influenza and pneumococcal vaccines
are recommended.
In addition, the presence of BRAF V600E mutations and
MS RO+ LCH in children was recognized as a factor that
negatively influences prognosis (71), but in adults with PLCH, the
BRAF V600E mutation was not associated with LCH presentation
and outcome (5).
LCH promotes the development of other neoplasms
originating from the lymphatic and hematopoietic systems,
including LCH overlapping with chronic myelogenous leukemia.
In a group of 132 adult patients with LCH, Ma et al. (82) found
that 32% were diagnosed with additional neoplasms, mostly
before [58%] and concurrently (21%) with LCH diagnosis. Lung
(18%), breast (18%), and colon (12%) cancers were the most
frequently detected additional neoplasms.
Pregnancy and Labor
Pregnancy does not worsen the course of PLCH, but delivery by
cesarean section is recommended due to the enhanced likelihood
of pneumothorax (83).
REFERENCES
1. Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J. Revised
classification of histiocytoses and neoplasms of the macrophage-dendritic cell
lineages. Blood. (2016) 127:2672–81. doi: 10.1182/blood-2016-01-690636
2. Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B,
Calicchio ML, et al. Recurrent BRAF mutations in langerhans cell
histiocytosis. Blood. (2010) 116:1919–23. doi: 10.1182/blood-2010-04-279083
3. Berres ML, Lim KP, Peters T, Price J, Takizawa H, Salmon H, et al.
BRAF-V600E expression in precursor versus differentiated dendritic cells
defines clinically distinct LCH risk groups. J Exp Med. (2014) 211:669–
83. doi: 10.1084/jem.20130977
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
Air Travel
Patients with PLCH have a higher risk of pneumothorax during
air travel. However, the risk is not high; approximately 1%
of patients exhibit this condition, and no severe instances of
pneumothorax have been reported thus far (84).
CONCLUSIONS
1. LCH is a rare disorder of unknown etiology caused by clonal
proliferation of geno- and phenotypically altered LCs.
2. It usually involves the bones, lungs, skin and pituitary,
lymphopoietic organs (lymph nodes, liver, spleen, bone
marrow), gastrointestinal tract, thyroid, CNS, and others.
3. PLCH may be as follows: isolated, anticipating even for many
years the occurrence of systemic changes, or from the very
beginning, the lungs may be one of the sites involved.
4. Tobacco smoke is a crucial causative factor for PLCH.
Smoking cessation is the most vital recommendation.
5. Chest HRCT has an outstanding importance in PLCH
diagnosis. Pulmonary lesions are the following: centrilobular
nodules, nodules with or without a central cavity, initially
thick-walled cysts of various shapes that may convolute,
forming the so-called clover leaves. The lesions are usually
(>90%) sparing the costophrenic angles.
6. The definite diagnosis of PLCH is based on adequate
clinical and radiological presentation and the identification
of LCs in the examined tissue samples showing in the
immunohistochemistry the presence of one of the following
antigens: CD207 (langerin), CD1a.
7. Treatment of LCH depends on extension of the disease.
Currently, the preferred cytostatic treatment option
includes cladribine or cytarabine. Lung transplantation
is recommended in patients with isolated PLCH with
respiratory insufficiency.
8. PLCH patients have a lower mean survival than individuals
of the same sex and age. Negative prognostic factors are age,
tobacco smoking, severe obstruction, lowered PaO2 , a higher
score in SGRQ, pulmonary hypertension, and multiple organ
involvement, particularly risk organs.
AUTHOR CONTRIBUTIONS
The author confirms being the sole contributor of this work and
has approved it for publication.
4. Roden AC, Hu X, Kip S, Parrilla Castellar ER, Rumilla KM, Vrana JA,
et al. BRAF V600E expression in langerhans cell histiocytosis: clinical
and immunohistochemical study on 25 pulmonary and 54 extrapulmonary
cases. Am J Surg Pathol. (2014) 38:548–51. doi: 10.1097/PAS.0000000000
000129
5. Jouenne F, Chevret S, Bugnet E, Clappier E, Lorillon G,
Meignin V, et al. Genetic landscape of adult Langerhans
cell histiocytosis with lung involvement. Eur Respir J. (2020)
55:1901190. doi: 10.1183/13993003.01190-2019
6. Goyal G, Young JR, Koster MJ, Tobin WO, Vassallo R, Ryu JH. The mayo
clinic histiocytosis working group consensus statement for the diagnosis
and evaluation of adult patients with histiocytic neoplasms: erdheim-chester
9 March 2021 | Volume 7 | Article 582581
Radzikowska
disease, langerhans cell histiocytosis, rosai-dorfman disease. Mayo Clinic Proc.
(2019) 94:2054–71. doi: 10.1016/j.mayocp.2019.02.023
7. Girschikofsky M, Arico M, Castillo D, Chu A, Doberauer C, Fichter J.
et al. Management of adult patients with langerhans cell histiocytosis:
recommendations from an expert panel on behalf of Euro-Histio-Net.
Orphanet J Rare Dis. (2013) 8:72. doi: 10.1186/1750-1172-8-72
8. Aricò M, Girschikofsky M, Généreau T, Klersy C, McClain K, Grois
N, et al. Langerhans cell histiocytosis in adults. Report from the
International Registry of the Histiocyte Society. Eur J Cancer. (2003) 39:2341–
8. doi: 10.1016/s0959-8049(03)00672-5
9. Vassallo R, Ryu JH, Schroeder DR, Decker PA, Limper AH. Clinical outcomes
of pulmonary Langerhans’-cell histiocytosis in adults. N Eng J Med. (2002)
346:484–90. doi: 10.1056/NEJMoa012087
10. Schönfeld N, Dirks K, Costabel U, Loddenkemper R. Wissenschaftliche
Arbeitsgemeinschaft für die Therapie von Lungenkrankheiten. A prospective
clinical multicentre study on adult pulmonary Langerhans’ cell histiocytosis.
Sarc Vasc Diffuse Lung Dis. (2012) 29:132–8. Available online at: https://
mattioli1885journals.com/index.php/sarcoidosis/article/view/2508
11. Elia D, Torre O, Cassandro R, Caminati A, Harari S. Pulmonary Langerhans
cell histiocytosis: a comprehensive analysis of 40 patients and literature review.
Eur J Int Med. (2015) 26:351–6. doi: 10.1016/j.ejim.2015.04.001
12. Picarsic J, Jaffe R. Nosology and pathology of Langerhans cell
histiocytosis. Hematol Oncol Clin North Am. (2015) 29:799–
82. doi: 10.1016/j.hoc.2015.06001
13. Ronceray L, Pötschger U, Janka G, Gadner H, Minkov M, German Society for
Pediatric, Hematology, and Oncology, Langerhans Cell Histiocytosis Study,
Group. Pulmonary involvement in pediatric-onset multisystem langerhans
cell histiocytosis: effect on course and outcome. J Pediatr. (2012) 161:129–
33.e333. doi: 10.1016/j.jpeds.2011.12.035
14. Le Louet S, Barkaoui MA, Miron J, Galambrun C, Aladjidi N, Chastagner
P, et al. Childhood Langerhans cell histiocytosis with severe lung
involvement: a nationwide cohort study. Orphanet J Rare Dis. (2020)
15:241. doi: 10.1186/s13023-020-01495-5
15. Goyal G, Shah MV, Hook CC, Wolanskyj AP, Call TG, Rech KL.
et al. Adult disseminated langerhans cell histiocytosis: incidence, racial
disparities and long-term outcomes. Br J Haematol. (2018) 182:579–
81. doi: 10.1111/bjh.14818
16. Tazi A, de Margerie C, Naccache JM, Fry S, Dominique S, Jouneau
S, et al. The natural history of adult pulmonary langerhans cell
histiocytosis: a prospective multicentre study. Orphanet J Rare Dis. (2015)
10:30. doi: 10.1186/s13023-015-0249-2
17. Radzikowska E, Błasińska-Przerwa K, Wiatr E, Bestry I, Langfort R,
Roszkowski-Sliz K. Pneumothorax in patients with pulmonary langerhans cell
histiocytosis. Lung. (2018) 196:715–20. doi: 10.1007/s00408-018-0155-1
18. Le Guen P, Chevret S, Bugnet E, de Margerie-Mellon C, Lorillon G, Seguin-
Givelet A, et al. Management and outcomes of pneumothorax in adult
patients with langerhans cell histiocytosis. Orphanet J Rare Dis. (2019)
14:229. doi: 10.1186/s13023-019-1203-5
19. Wang D, Cui L, Li ZG, Zhang L, Lian HY, Ma HH, et al. Clinical research
of pulmonary langerhans cell histiocytosis in children. Chinese Med J. (2018)
131:1793–8. doi: 10.4103/0366-6999.237400
20. Abla O, Rollins B, Ladisch S. Langerhans cell histiocytosis: progress and
controversies. Br J Haematol. (2019) 187:559–62. doi: 10.1111/bjh.16099
21. Liu H, Osterburg AR, Flury J, Swank Z, McGraw DW, Gupta N,
et al. MAPK mutations and cigarette smoke promote the pathogenesis
of pulmonary langerhans cell histiocytosis. JCI Insight. (2020)
5:e132048. doi: 10.1172/jci.insight.132048
22. Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, et al.
Interleukin-1 loop model for pathogenesis of langerhans cell histiocytosis. Cell
Comm Sig. (2015) 13:13. doi: 10.1186/s12964-015-0092-z
23. Suri HS, Yi ES, Nowakowski GS, Vassallo R. Pulmonary langerhans cell
histiocytosis. Orphanet J Rare Dis. (2012) 7:16. doi: 10.1186/1750-1172-7-16
24. Roden AC, Yi ES. Pulmonary langerhans cell histiocytosis: an update
from the pathologists’ perspective. Arch Pathol Lab Med. (2016) 140:230–
40. doi: 10.5858/arpa.2015-0246-RA
25. Alayed K, Medeiros LJ, Patel KP, Zuo Z, Li S, Verma S, et al. BRAF
and MAP2K1 mutations in Langerhans cell histiocytosis: a study of
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
50 cases. Human Pathol. (2016) 52:61–7. doi: 10.1016/j.humpath.201
5.12.029
26. Mourah S, How-Kit A, Meignin V, Gossot D, Lorillon G, Bugnet E, et al.
Recurrent NRAS mutations in pulmonary Langerhans cell histiocytosis. Eur
Respir J. (2016) 47:1785–96. doi: 10.1183/13993003.01677-2015
27. Ozer E, Sevinc A, Ince D, Yuzuguldu R, Olgun N. BRAF V600E
mutation: a significant biomarker for prediction of disease relapse in
pediatric langerhans cell histiocytosis. Pediatr Dev Pathol. (2019) 22:449–
55. doi: 10.1177/1093526619847859
28. Rodriguez-Galindo C, Allen CE. Langerhans cell histiocytosis. Blood. (2020)
135:1319–31. doi: 10.1182/blood.2019000934
29. Halbritter F, Farlik M, Schwentner R, Jug G, Fortelny N, Schnöller T,
et al. Epigenomics and single-cell sequencing define a developmental
hierarchy in langerhans cell histiocytosis. Cancer Discovery. (2019) 9:1406–
21. doi: 10.1158/2159-8290.CD-19-0138
30. Haroche J, Cohen-Aubart F, Rollins BJ, Donadieu J, Charlotte F, Idbaih A, et al.
Histiocytoses: emerging neoplasia behind inflammation. Lancet Oncol. (2017)
18:e113–25. doi: 10.1016/S1470-2045(17)30031-1
31. Mendez JL, Nadrous HF, Vassallo R, Decker PA, Ryu JH. Pneumothorax
in pulmonary Langerhans cell histiocytosis. Chest. (2004) 125:1028–
32. doi: 10.1378/chest.125.3.1028
32. Heiden GI, Sobral JB, Freitas CSG, Pereira de Albuquerque AL, Salge JM,
Kairalla RA, et al. Mechanisms of exercise limitation and prevalence of
pulmonary hypertension in pulmonary langerhans cell histiocytosis. Chest.
(2020) 158:2440–8. doi: 10.1016/j.chest.2020.05.609
33. Dauriat G, Mal H, Thabut G, Mornex JF, Bertocchi M, Tronc
F, et al. Lung transplantation for pulmonary langerhans’ cell
histiocytosis: a multicenter analysis. Transplantation. (2006)
81:746–50. doi: 10.1097/01.tp.0000200304.64613.af
34. Abbritti M, Mazzei MA, Bargagli E, Refini RM, Penza F, Perari MG,
et al. Utility of spiral CAT scan in the follow-up of patients with
pulmonary langerhans cell histiocytosis. Eur J Radiol. (2012) 81:1907–
12. doi: 10.1016/j.ejrad.2011.04.018
35. Kim HJ, Lee KS, Johkoh T, Tomiyama N, Lee HY, Han J, et al.
Pulmonary Langerhans cell histiocytosis in adults: high-resolution CT-
pathology comparisons and evolutional changes at CT. Eur Radiol. (2011)
21:1406–15. doi: 10.1007/s00330-011-2075-9
36. Albano D, Bosio G, Giubbini R, Bertagna F. Role of 18 F-FDG PET/CT
in patients affected by Langerhans cell histiocytosis. Jpn J Radiol. (2017)
35:574–83. doi: 10.1007/s11604-017-0668-1
37. Obert J, Vercellino L, Van Der Gucht A, de Margerie-Mellon C,
Bugnet E, Chevret S, et al. 18 F-fluorodeoxyglucose positron emission
tomography-computed tomography in the management of adult multisystem
Langerhans cell histiocytosis. Eur J Nucl Med Mol Imaging. (2017) 44:598–
610. doi: 10.1007/s00259-016-3521-3
38. Tazi A, Marc K, Dominique S, de Bazelaire C, Crestani B, Chinet
T, et al. Serial computed tomography and lung function testing in
pulmonary Langerhans’ cell histiocytosis. Eur Respir J. (2012) 40:905–
12. doi: 10.1183/09031936.00210711
39. Rolland-Debord C, Fry S, Giovannelli J, Langlois C, Bricout N, Aguilaniu B.
Physiologic determinants of exercise capacity in pulmonary langerhans
cell histiocytosis: a multidimensional analysis. PLoS ONE. (2017)
12:e0170035. doi: 10.1371/journal.pone.0170035
40. Harari S, Torre O, Cassandro R, Taveira-DaSilva AM, Moss J. Bronchoscopic
diagnosis of langerhans cell histiocytosis and lymphangioleiomyomatosis.
Respir Med. (2012) 106:1286–92. doi: 10.1016/j.rmed.2012.06.012
41. Baqir M, Vassallo R, Maldonado F, Yi ES, Ryu JH. Utility of bronchoscopy
in pulmonary Langerhans cell histiocytosis. J Bronch Intervent Pulm. (2013)
20:309–12. doi: 10.1097/LBR.0000000000000021
42. Fruchter O, Fridel L, El Raouf BA, Abdel-Rahman N, Rosengarten D, Kramer
MR. Histological diagnosis of interstitial lung diseases by cryo-transbronchial
biopsy. Respirology. (2014) 19:683–8. doi: 10.1111/resp.12296
43. Ravaglia C, Bonifazi M, Wells AU, Tomassetti S, Gurioli C, Piciucchi
S, et al. Safety and diagnostic yield of transbronchial lung cryobiopsy
in diffuse parenchymal lung diseases: a comparative study versus video-
assisted thoracoscopic lung biopsy and a systematic review of the literature.
Respiration. (2016) 91:215–27. doi: 10.1159/000444089
10 March 2021 | Volume 7 | Article 582581
Radzikowska
44. Lommatzsch M, Bratke K, Stoll P, Mülleneisen N, Prall F, Bier A, et al.
Bronchoalveolar lavage for the diagnosis of pulmonary langerhans cell
histiocytosis. Respir Med. (2016) 119:168–74. doi: 10.1016/j.rmed.2016.09.004
45. Auerswald U, Barth J, Magnussen H. Value of CD-1-positive cells in
bronchoalveolar lavage fluid for the diagnosis of pulmonary histiocytosis X.
Lung. (1991) 169:305–9. doi: 10.1007/BF02714167
46. Torre O, Harari S. The diagnosis of cystic lung diseases: a role for
bronchoalveolar lavage and transbronchial biopsy?. Respir Med. (2010)
104(Suppl 1):S81–5. doi: 10.1016/j.rmed.2010.03.021
47. Radzikowska E, Wiatr E, Błasińska-Przerwa K, Jeśkiewicz M, Langfort
R, Maksymiuk B, et al. Clinical features and outcome of adult patients
with pulmonary Langerhans cell histiocytosis. Eur Respir J. (2019) 54:PA
3683. doi: 10.1183/13993003.congress-2019
48. Bois MC, May AM, Vassallo R, Jenkins SM, Yi ES, Roden AC.
Morphometric study of pulmonary arterial changes in pulmonary
langerhans cell histiocytosis. Arch Pathol Lab Med. (2018)
142:929–37. doi: 10.5858/arpa.2017-0463-OA
49. Thierry A, Mouliere F, El Messaoudi S, Mollevi C, Lopez-Crapez E, Rolet
F, et al. Clinical validation of the detection of KRAS and BRAF mutations
from circulating tumor DNA. Nat Med. (2014) 20:430–5. doi: 10.1038/
nm.3511
50. Héritier S, Hélias-Rodzewicz Z, Lapillonne H, Terrones N, Garrigou
S, Normand C. Circulating cell-free BRAFV600E as a biomarker in
children with Langerhans cell histiocytosis. Br J Haemat. (2017) 178:457–
67. doi: 10.1111/bjh.14695
51. Lorillon G, Tazi A. How i manage pulmonary langerhans cell histiocytosis. Eur
Respir Rev. (2017) 26:170070. doi: 10.1183/16000617.0070-2017
52. Shaw B, Borchers M, Zander D, Gupta N. Pulmonary langerhans
cell histiocytosis. Sem Respir Critical Care Med. (2020) 41:269–
79. doi: 10.1055/s-0039-1700996
53. Derenzini E, Fina MP, Stefoni V, Pellegrini C, Venturini F, Broccoli
A. et al. MACOP-B regimen in the treatment of adult Langerhans cell
histiocytosis: experience on seven patients. Ann Oncol. (2010) 21:1173–
8. doi: 10.1093/annonc/mdp455
54. Duan MH, Han X, Li J, Zhang W, Zhu TN, Han B, et al. Comparison of
vindesine and prednisone and cyclophosphamide, etoposide, vindesine,
and prednisone as first-line treatment for adult Langerhans cell
histiocytosis: a single-center retrospective study. Leukemia Res. (2016)
42:43–6. doi: 10.1016/j.leukres.2016.01.012
55. Morimoto A, Shimazaki C, Takahashi S, Yoshikawa K, Nishimura R, Wakita
H, et al. Therapeutic outcome of multifocal langerhans cell histiocytosis in
adults treated with the special c regimen formulated by the Japan LCH
study group. Int J Hematol. (2013) 97:103–8. doi: 10.1007/s12185-012-
1245-0
56. Ng Wing Tin S, Martin-Duverneuil N, Idbaih A, Garel C, Ribeiro M, Parker
JL, et al. Efficacy of vinblastine in central nervous system Langerhans cell
histiocytosis: a nationwide retrospective study. Orphanet J Rare Dis. (2011)
6:83. doi: 10.1186/1750-1172-6-83
57. Tazi A, Lorillon G, Haroche J, Neel A, Dominique S, Aouba A,
et al. Vinblastine chemotherapy in adult patients with langerhans cell
histiocytosis: a multicenter retrospective study. Orphanet J Rare Dis. (2017)
12:95. doi: 10.1186/s13023-017-0651-z
58. Cantu MA, Lupo PJ, Bilgi M, Hicks MJ, Allen CE, McClain KL. Optimal
therapy for adults with langerhans cell histiocytosis bone lesions. PLoS ONE.
(2012) 7:e43257. doi: 10.1371/journal.pone.0043257
59. Néel A, Artifoni M, Fontenoy AM, Tessoulin B, Lorillon G, Cohen-Aubart F,
et al. Long-term efficacy and safety of 2CdA (cladribine) in extra-pulmonary
adult-onset Langerhans cell histiocytosis: analysis of 23 cases from the French
Histiocytosis Group and systematic literature review. Br J Haemtol. (2020)
189:869–78. doi: 10.1111/bjh.16449
60. Saven A, Burian C. Cladribine activity in adult Langerhans-cell histiocytosis.
Blood. (1999) 93:4125–30.
61. Grobost V, Khouatra C, Lazor R, Cordier JF, Cottin V. Effectiveness of
cladribine therapy in patients with pulmonary langerhans cell histiocytosis.
Orphanet J Rare Dis. (2014) 9:191. doi: 10.1186/s13023-014-0191-8
62. Pardanani A, Phyliky RL, Li CY, Tefferi A. 2-Chlorodeoxyadenosine therapy
for disseminated Langerhans cell histiocytosis. Mayo Clin Proc. (2003) 78:301–
6. doi: 10.4065/78.3.301
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
63. Adam Z, Szturz P, Vaníček J, Moulis M, Pour L, Krej,čí M, et al. Cladribine
(2-chlorodeoxyadenosine) in frontline chemotherapy for adult Langerhans
cell histiocytosis: a single-center study of seven cases. Acta Oncol. (2013)
52:994–1001. doi: 10.3109/0284186X.2012.716164
64. Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte
F, et al. Dramatic efficacy of vemurafenib in both multisystemic
and refractory Erdheim-Chester disease and langerhans cell
histiocytosis harboring the BRAF V600E mutation. Blood. (2013)
121:1495–500. doi: 10.1182/blood-2012-07-446286
65. Donadieu J, Larabi IA, Tardieu M, Visser J, Hutter C, Sieni E, et al.
Vemurafenib for refractory multisystem langerhans cell histiocytosis in
children: an international observational study. J Clin Oncol. (2019) 37:2857–
65. doi: 10.1200/JCO.19.00456
66. Hazim AZ, Ruan GJ, Ravindran A, Abeykoon JP, Scheckel C, Vassallo R, et al.
Efficacy of BRAF-inhibitor therapy in BRAFV600E -mutated adult langerhans
cell histiocytosis. Oncologist. (2020) 25:1001–4. doi: 10.1002/onco.13541
67. Diamond EL, Subbiah V, Lockhart AC, Blay JY, Puzanov I. Chau,
et al. Vemurafenib for BRAF V600-mutant erdheim-chester disease and
langerhans cell histiocytosis: analysis of data from the histology-independent,
phase 2, open-label VE-BASKET study. JAMA Oncol. (2018) 4:384–
8. doi: 10.1001/jamaoncol.2017.5029
68. Bhatia A, Ulaner G, Rampal R, Hyman DM, Abdel-Wahab O, Durham
BH, et al. Single-agent dabrafenib for BRAFV600E -mutated histiocytosis.
Haematologica. (2018) 103:e177–80. doi: 10.3324/haematol.2017.1
85298
69. Diamond EL, Durham BH, Ulaner GA, Drill E, Buthorn J, Ki M, et al. Efficacy
of MEK inhibition in patients with histiocytic neoplasms. Nature. (2019)
567:521–4. doi: 10.1038/s41586-019-1012-y
70. Hyman DM, Puzanov I, Subbiah V, Faris JE, Chau I, Blay JY, et al.
Vemurafenib in multiple nonmelanoma Cancers with BRAF V600 Mutations.
N Engl J Med. (2015) 373:726–36. doi: 10.1056/NEJMoa1502309
71. Héritier S, Emile JF, Barkaoui MA, Thomas C, Fraitag S, Boudjemaa S,
et al. BRAF mutation correlates with high-risk langerhans cell histiocytosis
and increased resistance to first-line therapy. J Clin Oncol. (2016) 34:3023–
30. doi: 10.1200/JCO.2015.65.9508
72. Lorillon G, Jouenne F, Baroudjian B, de Margerie-Mellon C, Vercellino L,
Meignin V, et al. Response to trametinib of a pulmonary langerhans cell
histiocytosis harboring a MAP2K1 deletion. Am J Respir Crit Care Med. (2018)
198:675–8. doi: 10.1164/rccm.201802-0275LE
73. Awada G, Seremet T, Fostier K, Everaert H, Neyns B. Long-
term disease control of Langerhans cell histiocytosis using
combined BRAF and MEK inhibition. Blood Adv. (2018)
2:2156–8. doi: 10.1182/bloodadvances.201802178
74. Montella L, Insabato L, Palmieri G. Imatinib mesylate for
cerebral Langerhans’-cell histiocytosis. NEJM. (2004) 351:1034–
5. doi: 10.1056/NEJM200409023511022
75. Janku F, Amin HM, Yang D, Garrido-Laguna I, Trent JC, Kurzrock R.
Response of histiocytoses to imatinib mesylate: fire to ashes. J Clin Oncol.
(2010) 28:e633–e636. doi: 10.1200/JCO.2010.29.9073
76. Wagner C, Mohme H, Krömer-Olbrisch T, Stadler R, Goerdt S,
Kurzen H. Langerhans cell histiocytosis: treatment failure with
imatinib. Arch Derm. (2009) 145:949–50. doi: 10.1001/archdermatol.20
09.164
77. Gupta N, Langenderfer D, McCormack FX, Schauer DP, Eckman MH. Chest
computed tomographic image screening for cystic lung diseases in patients
with spontaneous pneumothorax is cost effective. Ann Am Thorac Soc. (2017)
14:17–25. doi: 10.1513/AnnalsATS.201606-459OC
78. Le Pavec J, Lorillon G, Jaïs X, Tcherakian C, Feuillet S, Dorfmüller
P, et al. Pulmonary langerhans cell histiocytosis-associated pulmonary
hypertension: clinical characteristics and impact of pulmonary arterial
hypertension therapies. Chest. (2012) 142:1150–7. doi: 10.1378/chest.1
1-2490
79. May A, Kane G, Yi E, Frantz R, Vassallo R. Dramatic and sustained
responsiveness of pulmonary langerhans cell histiocytosis-associated
pulmonary hypertension to vasodilator therapy. Respir Med Case Rep. (2014)
14:13–5. doi: 10.1016/j.rmcr.2014.11.005
80. Nemoto K, Oh-Ishi S, Inui T, Nakazawa M, Hyodo K, Nakajima M,
et al. Long-term improvement during tadalafil therapy in a patient
11 March 2021 | Volume 7 | Article 582581
Radzikowska
with pulmonary hypertension secondary to pulmonary langerhans cell
histiocytosis. Respir Med Case Rep. (2016) 18:54–7. doi: 10.1016/j.rmcr.201
6.04.008
81. Wajda N, Zhu Z, Jandarov R, Dilling DF, Gupta N. Clinical
outcomes and survival following lung transplantation in patients
with pulmonary Langerhans cell histiocytosis. Respirology. (2020)
25:644–50. doi: 10.1111/resp.13671
82. Ma J, Laird JH, Chau KW, Chelius MR, Lok BH, Yahalom J. Langerhans cell
histiocytosis in adults is associated with a high prevalence of hematologic
and solid malignancies. Cancer Med. (2019) 8:58–66. doi: 10.1002/ca
m4.1844
83. Radzikowska E, Wiatr E, Franczuk M, Bestry I, Roszkowski-Sli,z K. Lung
function in pregnancy in langerhans cell histiocytosis. Adv Exp Med Biol.
(2018) 1023:73–83. doi: 10.1007/5584_2017_72
Frontiers in Medicine | www.frontiersin.org
Update on PLCH
84. Singla A, Kopras EJ, Gupta N. Spontaneous pneumothorax and air travel
in pulmonary Langerhans cell histiocytosis: a patient survey. Respir Invest.
(2019) 57:582–9. doi: 10.1016/j.resinv.2019.07.004
Conflict of Interest: The author declares that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2021 Radzikowska. This is an open-access article distributed under the
terms of the Creative Commons Attribution License (CC BY). The use, distribution
or reproduction in other forums is permitted, provided the original author(s) and
the copyright owner(s) are credited and that the original publication in this journal
is cited, in accordance with accepted academic practice. No use, distribution or
reproduction is permitted which does not comply with these terms.
12 March 2021 | Volume 7 | Article 582581